In nature, the molecular recognition based on biological receptors (such as enzymes, antibodies, etc.) plays a decisive role in most biological processes (such as immune responses, ligand-receptor interaction, and enzyme catalysis). How to develop synthetic receptors with an affinity and specificity approaching those of biological receptors has been a significant challenge for the contemporary chemists. So far, many low molecular weight organic receptors have been prepared (F. Hof, S. L. Craig, C. Nuckolls, J. Rebek Jr., Angew. Chem. Int. Ed. 2002, 41, 1488-1508; D. M. Vriezema, M. C. Aragonés, J. A. A. W. Elemans, J. J. L. M. Cornelissen, A. E. Rowan, R. J. M. Nolte, Chem. Rev. 2005, 105, 1445-1490). The construction of such synthetic receptors, however, usually requires complicated multi-step synthesis, which severely limits their broad applications. Developing other synthetically more accessible receptors has become a hot research topic in recent years.
Molecular imprinting technique is a facile and efficient new method to prepare polymer receptors with specific molecular recognition sites (H. Zhang, L. Ye, K. Mosbach, J. Mol. Recognit. 2006, 19, 248-259). The molecularly imprinted polymers (simply MIPs) generated by this technique have attracted enormous attention due to their high specific molecular recognition ability, ease of preparation, and good thermal and chemical stability. In the present, molecular imprinting technique has become a straightforward and efficient way to obtaining biomimetic synthetic receptors. One of the most distinct characteristics of the molecular imprinting process is its generality, which offers the freedom to prepare MIPs for a wide range of templates without appreciably changing the synthetic protocols. So far, the application studies of the MIPs have been extended to many areas, including chromatographic stationary-phase, solid-phase extraction, immunoassays, biomimetic sensors, artificial enzymes, organic synthesis, and drug delivery. They have shown great potential for applications in the fields of food safety and environmental monitoring. The ultimate goal of the molecular imprinting study is to generate MIPs that are comparable with biological receptors, which can eventually replace the biological receptors in practical applications.
Despite the fact that significant progress has been achieved in the molecular imprinting field and some MIPs have become commercially available for some specific applications (e.g., solid-phase extraction), there still exist some key problems and challenges in this area, which significantly limits their broad practical applications. One of such challenges is how to prepare MIPs with excellent specific recognition ability toward small organic analytes (most of the environmental pollutants, drugs, antibiotics, pesticides, and herbicides are small organic molecules) in aqueous media. The previously developed MIPs that target small organic molecules normally only show good molecular recognition ability in organic solvents, and those truly compatible with aqueous samples are rather rare. It is, however, certainly worth replacing organic solvents with water from the viewpoint of many aspects such as economy, ecology, and environmental protection. In addition, it is definitely necessary to use water as the solvent for the potential application of the MIPs in the field of biotechnology. Furthermore, the use of MIPs capable of efficient molecular recognition in aqueous media can help achieve the goal of direct and rapid sensing of small organic analytes in their practical applications in such areas as environmental and food monitoring and clinical diagnostics. Although some advances have been made in this aspect by using specifically designed functional monomers (G. Wulff, R. Schöonfeld, Adv. Mater 1998, 10, 957-959; H. Asanuma, T. Hishiya, M. Komiyama, Adv. Mater 2000, 12, 1019-1030; P. Manesiotis, A. J. Hall, J. Courtois, K. Irgum, B. Sellergren, Angew. Chem. Int. Ed. 2005, 44, 3902-3906; J. L. Urraca, A. J. Hall, M. C. Moreno-Bondi, B. Sellergren, Angew. Chem. Int. Ed. 2006, 45, 5158-5161), by using traditional molecular imprinting method (L. I. Anderson, R. Müller, G. Vlatakis, K. Mosbach, Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 4788-4792; J. G. Karlsson, L. I. Andersson, I. A. Nicholls, Anal. Chim. Acta 2001, 435, 57-64), or by adding hydrophilic co-monomers into the molecular imprinting systems (B. Dirion, Z. Cobb, E. Schillinger, L. I. Andersson, B. Sellergren, J. Am. Chem. Soc. 2003, 125, 15101-15109), the preparation of MIPs compatible with pure biological samples remains a challenging task in the present.
It is well known that biological samples, and in particular pure biological samples, have rather complex components (for example, biological samples such as milk and serum contain a large amount of proteins), which makes it very difficult for the MIPs to specifically recognize small organic analytes in real biological samples. It is noted that although there have been many reports on the application of MIPs as solid-phase extraction materials for the separation of target analytes in real biological matrices (B. Sellergren, Anal. Chem. 1994, 66, 1578-1582; E. Caro, R. M. Marcé, F. Borrull, P. A. G. Cormack, D. C. Sherrington, Trend. Anal. Chem. 2006, 25, 143-154; B. Tse Sum Bui, K. Haupt, Anal. Bioanal. Chem. 2010, 398, 2481-2492; E. Turiel, A. Martín-Esteban, Anal. Chim. Acta 2010, 668, 87-99), however, the selectivity of the MIPs in this case is mainly controlled by the washing solvents used in the extraction processes. This is much easier than the direct use of MIPs for the molecular recognition in real matrices, as the latter case is mainly fixed by the nature of MIPs (V. Pichon, F. Chapuis-Hugon, Anal. Chim. Acta 2008, 622, 48-61).
Recently, the inventors reported the one-pot synthesis of pure water-compatible MIP microspheres with surface-grafted hydrophilic polymer brushes through the introduction of hydrophilic macromolecular chain transfer agents into the reversible addition-fragmentation chain transfer (RAFT) precipitation polymerization system (G. Pan, Y. Zhang, Y. Ma, C. Li, H. Zhang, Angew. Chem. Int. Ed. 2011, 50, 11731-11734). The MIP particles prepared by the above method, however, are of micrometer sizes, and in spite of their compatibility with normal aqueous samples, they cannot be used for the direct analyses of biological samples because of the significant adsorption of proteins in biological samples onto the surfaces of the MIP microspheres. Therefore, the inventors successfully prepared MIP nanoparticles with surface-grafted hydrophilic polymer brushes that are compatible with biological samples, and in particular pure biological samples in a one-pot method on the basis of the above work. The nanosized volumes imparted these hydrophilic MIP nanoparticles with excellent water dispersion stability, which paved the way for their applications in such areas as environmental monitoring, food safety, and clinical diagnostics.